title: β-Catenin activation synergizes with Pten loss and Myc overexpression in Notch-independent T-ALL.
abstract: Wnt signaling is important for T-cell differentiation at the early CD4(-)CD8(-) stage and is subsequently downregulated with maturation. To assess the importance of this downregulation, we generated a mouse line (R26-βcat) in which high levels of active β-catenin are maintained throughout T-cell development. Young R26-βcat mice show a differentiation block at the CD4(+)CD8(+) double-positive (DP) stage. These DP cells exhibit impaired apoptosis upon irradiation or dexamethasone treatment. All R26-βcat mice develop T-cell leukemias at 5 to 6 months of age. R26-βcat leukemias remain dependent on β-catenin function but lack Notch pathway activation. They exhibit recurrent secondary genomic rearrangements that lead to Myc overexpression and loss of Pten activity. Because β-catenin activation and Myc translocations were previously found in murine T-cell acute lymphoblastic leukemias (T-ALLs) deficient for Pten, our results suggest that activation of the canonical Wnt pathway is associated with a subtype of Notch-independent T-ALLs that bear Myc gene rearrangements and Pten mutations.
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, INSERM U964, Centre National de la Recherche Scientifique UMR 7104, Université de Strasbourg, Illkirch, France.
authors.forename: Deepika
authors.initials: D
authors.lastname: Kaveri
authors.forename: Philippe
authors.initials: P
authors.lastname: Kastner
authors.forename: Doulaye
authors.initials: D
authors.lastname: Dembélé
authors.forename: Claus
authors.initials: C
authors.lastname: Nerlov
authors.forename: Susan
authors.initials: S
authors.lastname: Chan
authors.forename: Peggy
authors.initials: P
authors.lastname: Kirstetter
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D017353:Gene Deletion; D015973:Gene Expression Regulation, Leukemic; D016259:Genes, myc / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000502:physiology; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D051880:Receptors, Notch / Q000235:genetics / Q000502:physiology*; D013601:T-Lymphocytes / Q000378:metabolism / Q000502:physiology; D015854:Up-Regulation / Q000235:genetics; D060449:Wnt Signaling Pathway / Q000235:genetics / Q000502:physiology; D051176:beta Catenin / Q000819:agonists / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D051880:Receptors, Notch; D051176:beta Catenin; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse